Introduction: Haemostasis is the arrest of bleeding. In recent years, in-vitro studies have suggested that secondary haemostasis (blood coagulation) is subject to activation by reactive oxygen species (ROS). It is known that patients who suffer from vascular disease are typically hypoxaemic and in the case of peripheral occlusive artery disease (POAD), physical exercise is used to improve symptom free mobility in the affected limbs. Hypoxia and physical exercise are two potent independent and synergistic initiators of ROS. We identified a clear need for in-vivo analysis of this novel area of research. Aims: There were two main aims of this research. 1. To explore the in-vivo influences of inspiratory hypoxia and physical exercise on biomarkers of haemostasis; and in doing so and subsequently carry out a randomised double blind placebo control trial to explore the interaction between oxidative stress (ROS accumulation) and haemostasis. Hypothesis: It was hypothesised that hypoxia and exercise would be independently and synergistically associated with an increase in oxidative stress, resulting in coagulation activation. We hypothesised that intervention with free radical reaction-chain breaking antioxidant vitamins would attenuate oxidative stress and thus attenuate the activation of coagulation. Methods: study 1 - Healthy males were subjected to six hours of normobaric hypoxia (12% inspired oxygen) and then a physical exercise challenge to exhaustion (cycling ramp-test). Citrated plasma was collected pre hypoxic exposure, post six hours of exposure, then immediately post exercise and analysed for routine clinical markers of coagulation (aPTT, PT, TT and fibrinogen) and analysed with and without correction for plasma volume shift. Data were analysed using a one-factor repeated measures ANOVA incorporating one within (condition: time point) subjects factor. Following a significant main effect and interaction, paired samples t-tests were employed to make post hoc comparisons at each level of the within-subjects factor. Study! - Healthy males were subjected to a double blind, randomised, placebo controlled intervention with vitamin C (a water soluble) and vitamin E (a lipid soluble), two ROS-scavenging, chain breaking antioxidants. The intervention lasted eight weeks to insure membrane enrichment with antioxidants. The methods of study one were repeated but with a pre-intervention time point added and the addition of two extra markers of thrombin generation (PF1+2 and T-AT). Data were analysed using a two-factor mixed ANOVA incorporating one between (group: antioxidant intervention vs. placebo control) and one within (condition: time point) subjects factor. Following a significant main effect and interaction, a paired samples t-test was used to make post hoc comparisons at each level of the within-subjects factor, with the alpha level Bonferroni corrected for multiple comparisons Between-group comparisons were assessed using independent samples t-tcsts applied to each level of the between-subjects factor. Results: Study 1 - Hypoxia was not associated with activation of coagulation. Physical exercise increased the activity of contact factor coagulation pathway activation. Study 2 - The intervention increased thrombin generation in the antioxidant group. This was met with an antagonistic antithrombin activation. Hypoxia did not impact the placebo group, but normalised the thrombin generation of the antioxidant group. Physical exercise increased contact factor pathway (CFP) as per study 1, but thrombin generation was unaltered. Hypoxia suppressed fibrinolysis post exercise, which is known to be activated in normoxic exercise. Discussion: hi study one, hypoxia alone did not activate coagulation. We hypothesised that this could be tentative evidence of a ROS concentration threshold for activation since once exercise was superimposed the accumulation of ROS activated the CFP. Correction for changes in plasma volume nullified the increased activity of the CFP. Corrections for shifts in plasma volume are routinely ignored in the literature and this was a novel finding. Study 2 was the first intervention of its kind. The increase in thrombin generation pre-post intervention with antioxidants suggests compelling evidence of in-vivo regulation of coagulation by ROS. But the direction of change was completely contrary to the original hypothesis. The confirmation that hypoxia does not activate coagulation is important, especially given the controversy surrounding long-haul flight deep vein thrombosis. Interestingly, exercise did not increase thrombin generation, despite the increase in the CFP. These findings suggest haemostasis is indeed subject to control by the body's redox state invivo via an as of yet, unknown mechanism.

Thesis (doctoral)--Lund University, 1994. / Added t.p. with thesis statement inserted.

Thesis (M. Phil.)--University of Hong Kong, 2005. / Title proper from title frame. Also available in printed format.

published_or_final_version / abstract / Paediatrics and Adolescent Medicine / Master / Master of Philosophy

An individual who is diagnosed with an inherited bleeding disorder is expected to manage his or her condition on a daily basis. This chronic situation can totally disrupt psychosocial functioning and make it more difficult to adjust to the illness. Other researchers have studied this phenomenon in various other chronic illnesses; however, not in individuals with inherited bleeding disorders (Akkasilpa, et al, 2000, Pollack, 1989a, 1989b). Psychosocial problems are not restricted to individuals with one chronic illness and clinically, it is noted that some individuals adjust to chronic diseases better than others. Individuals living with inherited bleeding disorders may also have other chronic illnesses such as hypertension, asthma, diabetes mellitus (DM), congestive heart failure (CHF), arthritis, and hepatitis A, B, C and/or HN. The aims of this study are to describe health stressors, health related hardiness, perception of illness impact, self perception of health status and psychosocial adjustment to illness in individuals living with an inherited bleeding disorder; to determine relationships between demographic and illness variables, health stressors, health related hardiness, perception of illness impact, self­ perception of health status and psychosocial adjustment to illness; and to determine if perception of illness impact has a direct and/or mediating effect on the relationship between health stressors, health related hardiness, and self-perception ofhealth status and psychosocial adjustment to illness. A cross sectional survey design was used in this study. Sixty individuals of predominantly Asian Pacific Islander ethnicity diagnosed with hemophilia, von Willebrand's Disease, Factor V or as hemophilia carriers comprised the sample which was drawn from the Hemophilia Treatment Center of Hawaii. All participants were asked to complete five questionnaires: Demographic form and illness information, health related hardiness scale (Pollock, 1990), perception of illness impact scale, self-perception of health status and psychosocial adjustment to illness scale (Derogatis, 1990). Higher health stressors were associated with higher perception of illness impact, lower perception of health status and poorer psychosocial adjustment to illness. Individuals with higher hardiness were better adjusted to their illness. Higher perception of illness impact was associated with lower self-perception of health status and poorer psychosocial adjustment to illness. Higher self-perception of health status was associated with better psychosocial adjustment to illness. Perception of illness impact did mediate the relationship between health related hardiness and psychosocial adjustment to illness. Perception of illness impact did not mediate the relationship between health stressors and psychosocial adjustment to illness, between health stressors and self-perception of health status, and between health related hardiness and self-perception of health status. The knowledge generated from this study has the potential to impact the existing practices in improving evidence-based nursing practice in caring for individuals with inherited bleeding disorders. Future research is indicated with a large sample to determine differences between diagnosed individuals and carriers, between various Asian Pacific Islander cultural groups, and to determine replicability of the findings from this smaller study sample.

by Chan Po Kwok. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1997. / Includes bibliographical references (leaves 132-140). / Abstract --- p.i / Acknowledgement --- p.iii / Publication --- p.iv / Abbreviations --- p.v / Table of Contents --- p.vi / Chapter Chapter 1 --- Introduction / Chapter Section a --- Blood Coagulation --- p.1 / Chapter Section b --- The role of factor XII --- p.4 / Chapter Section c --- Genomic organisation of the human factor XII gene --- p.8 / Chapter Section d --- Protein structure of the human factor XII --- p.12 / Chapter Section e --- Mutations in factor XII --- p.16 / Chapter Section f --- Methods to detect mutations --- p.25 / Chapter Section g --- About the patient with factor XII deficiency --- p.29 / Chapter Section h --- Strategies used in this study --- p.30 / Chapter Chapter 2 --- Methods and Materials / Chapter Section a --- Genomic DNA extraction --- p.33 / Chapter Section b --- Polymerase chain reaction amplification --- p.34 / Chapter Section c --- Cycle sequencing --- p.35 / Chapter Section d --- Restriction enzyme digestion and cloning of PCR products --- p.36 / Chapter Section e --- Reverse transcription and polymerase chain reaction of factor XII ectopic transcript --- p.36 / Chapter Section f --- Subcloning of 95-bp novel fragment --- p.38 / Chapter Section g --- Gel mobility shift assay --- p.39 / Chapter Chapter 3 --- Results / Chapter Section a --- Analysis of the catalytic region of the human factor XII --- p.41 / Chapter Section b --- Ectopic transcript of factor XII in peripheral blood lymphocytes --- p.65 / Chapter Section c --- Analysis of 3'end untranslated region of factor XII gene --- p.70 / Chapter Section d --- Analysis of 5' flanking region of factor XII gene --- p.75 / Chapter Section e --- Analysis of intron B --- p.94 / Chapter Section f --- Analysis of 5'-b PCR product --- p.98 / Chapter Chapter 4 --- Discussions / Chapter Section a --- Mutations in the coding sequence of factor XII gene --- p.107 / Chapter Section b --- Ectopic transcript of factor XII in lymphocytes --- p.113 / Chapter Section c --- The 3'untranslated region of factor XII gene --- p.116 / Chapter Section d --- The 5'flanking region of factor XII gene --- p.117 / Chapter Section e --- Other possible explanations of undetectable factor XII mRNA --- p.120 / Chapter Section f --- The 95-bp novel sequence in ´5ة flanking region --- p.123 / Chapter Section g --- Technical difficulties --- p.126 / Chapter Section h --- Future study --- p.130 / Chapter Chapter 5 --- References --- p.132 / List of Tables --- p.137 / List of Figures --- p.138

Thesis (M.S.)--Georgia State University, 2005. / Title from title screen. Roberta Attanasio, committee chair; P.C. Tai, W.C. Hooper, committee members. Electronic text (57 p. : col. ill.) : digital, PDF file. Description based on contents viewed Aug. 15, 2007. Includes bibliographical references (p. 55-57).

Trata-se de um estudo randomizado para avaliação de factibilidade conduzido entre dezembro de 2015 a janeiro de 2017 com pacientes de trauma grave (Index of Shock Severity [ISS] >= 15), admitidos na sala de emergência de um grande centro de trauma. À admissão os pacientes selecionados apresentavam hipofibrinogenemia qualitativa (FIBTEM A5 <= 9 mm) além de hipotensão (pressão arterial sistólica [PAs] < 90mmHg) e taquicardia (frequência cardíaca [FC] > 100 bpm). O desfecho primário foi avaliar factibilidade, definida como a proporção dos pacientes que receberam o tratamento alocado em até 60 minutos após a randomização: reposição de concentrado de fibrinogênio (CF) na dose de 50 mg/kg de peso corporal no grupo intervenção e não receber reposição de fibrinogênio no grupo controle. Uma lista de alocação randomizada dos tratamentos foi gerada por estatístico utilizando \"software\" apropriado. A alocação do tratamento foi realizada utilizando-se envelopes opacos lacrados, numerados sequencialmente. Não houve cegamento por inviabilidade de execução logística. Um total de 84 pacientes foram avaliados para elegibilidade, 52 foram excluídos e 32 foram randomizados, sendo alocados dezesseis em cada grupo. A maioria dos pacientes selecionados foram homens (87,5%), na quarta década de vida (42 ± 15,5) e com ISS de 32 ± 7,2. Todos os pacientes incluídos receberam o tratamento conforme alocado em até 60 minutos após a randomização (100%; IC 95%, 86,7% a 100%). O fibrinogênio sérico na sala operatória (SO) foi maior no grupo intervenção em comparação ao grupo controle (190,4 ± 85,5 vs 130,2 ± 51,1; p=0,04), mas não na chegada à UTI (330,8 ± 165,1 vs 280,3 ± 130,3; p=0,43). Houve diferença estatística significativa no desfecho secundário exploratório tempo médio de internação em UTI entre o grupo experimental e grupo controle (mediana 8, intervalo interquartil [IIQ] 5,75 - 10,0 vs mediana 11, IIQ 8,5 - 16,0; p=0,02). Não houve diferença estatística em qualquer outro desfecho clínico avaliado. Não houve danos ou efeitos indesejáveis. Concluiuse que é possível realizar um estudo clínico randomizado em contexto de emergência com reposição precoce de fibrinogênio através do concentrado de fibrinogênio. O estudo foi registrado no ClinicalTrials.gov (NCT02864875) / This is a randomized feasibility trial conducted between December 2015 and January 2017 with severe trauma patients (Index of Shock Severity [ISS] >= 15) admitted to the emergency room of a large trauma center. At admission patients presented qualitative hypofibrinogenemia (FIBTEM A5 <= 9 mm), hypotension (systolic blood pressure < 90 mmHg) and tachycardia (heart rate > 100 bpm). The primary outcome was feasibility assessed by the proportion of patients receiving the allocated treatment up to 60 minutes after randomization meaning receive replacement through fibrinogen concentrate (50mg per kg of body weight) by the intervention group and not to receive an early replacement of fibrinogen by control group. A randomized allocation list of treatments was generated by a statistician using an appropriate software. The treatment allocation was performed using sealed opaque envelopes, numbered sequentially. There was no blindness because it was no feasible in our institution. A total of 84 patients were assessed for eligibility, 52 were excluded and 32 were randomized (16 allocated to each group). The majority of patients selected were men (87,5%), in the fourth decade of life (42 ± 15,5) with ISS of 32 ± 7,2. All randomized patients received treatment as allocated up to 60 minutes after randomization (100%, 95% CI, 86,7% to 100%). Serum fibrinogen was higher in the intervention group on operating room (OR) (190,4 ± 85,5 vs 130,2 ± 51,1; p=0,04) comparing to control group but this difference was not seen on intensive care unit (ICU) (330,8 ± 165,1 vs 280,3 ± 130,3; p=0,43). The length of ICU stay was smaller in the intervention group compared to the control group (median 8, IQR 5,75 - 10,0 vs median 11, IQR 8,5 - 16,0; p=0,02). There was no difference between groups in any other clinical outcomes. We registered no adverse effects related to treatment in both groups. We concluded that it is possible to perform a randomized clinical trial in an emergency setting with early fibrinogen replacement through the fibrinogen concentrate. The study was enrolled in ClinicalTrials.gov (NCT02864875)

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

Thesis (PhD.(Anatomy)--Faculty of Health Sciences)-University of Pretoria, 2007. / Includes bibliographical references.